1. Field of Invention
The present invention relates generally to the fields of pharmacology, urology and psychiatry and to methods of treating sexual dysfunction. More specifically, this invention provides methods for the use of certain carbamate compounds for use alone or in combination with other medications for the treatment of sexual dysfunction in human females or males
2. Description of Related Art
Masters and Johnson defined sexual dysfunction as “the persistent impairment of normal or usual patterns of sexual interest and/or response” (Masters et al., Human Sexual Response, Boston, Mass.: Little, Brown and Co. 1966). The problem came to national attention when the results of the National Health and Societal Life Survey were published in 1999. Interviews with over 3000 American men and women aged 18-59 revealed that 31% of men and 43% of women (about 40 million) experienced some degree of sexual dysfunction. The scope of the problem was such that it was said to “warrant recognition as a significant public health concern.” See Laumann et al., “Sexual Dysfunction in the United States: prevalence and predictors,” JAMA 281:537 (1999). Although sexual dysfunction rarely threatens physical health, it can take a heavy psychological toll, bringing on depression, anxiety, and debilitating feelings of inadequacy.
Sexual dysfunction (SD) is a significant clinical problem that can affect both males and females. The causes of SD may be both organic as well as psychological. Organic aspects of SD are typically caused by underlying vascular diseases, such as those associated with hypertension or diabetes mellitus, by prescription medication and/or by psychiatric disease such as depression. Physiological factors include fear, performance anxiety and interpersonal conflict. SD impairs sexual performance, diminishes self-esteem and disrupts personal relationships thereby inducing personal distress. In the clinic, SD disorders have been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (Melman et al 1999 J. Urology 161, 5-11). FSD is best defined as the difficulty or inability of a woman to find satisfaction in sexual expression.
Male sexual dysfunction (MSD) is generally associated with either erectile dysfunction, also known as male erectile dysfunction (MED) and/or ejaculatory disorders such as premature ejaculation or rapid ejaculation (PED), anorgasmia (unable to achieve orgasm) or male orgasmic disorder (MOD) or desire disorders such as hypoactive sexual desire disorder (lack of interest in sex) (HSDD) and can result from a variety of causes, including physical illness, depression, hormonal abnormality or medications that affect libido or performance.
Recent studies suggest that, at least, 43% of woman have some form of sexual dysfunction (See above, Lauman et al. JAMA, 281:537, 1999). These can be categorized into four main areas: 1) sexual desire disorders, namely hypoactive sexual desire or sexual aversion disorder; 2) sexual arousal disorders; 3) orgasmic disorders; and 4) sexual pain disorders which include dyspaureunia and vaginismus.
The dominant category of female sexual dysfunction (FSD) is female sexual arousal disorder (FSAD), which affects up to 75% of women diagnosed with FSD.
The categories of female sexual dysfunction (FSD) are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (see S R Leiblum, (1998), Definition and Classification of Female Sexual Disorders, Int. J. Impotence Res., 10, S104-S106). Sexual desire or libido is the drive for sexual expression. Its manifestations include sexual thoughts and fantasies. Arousal includes the vascular response to sexual stimulation, an important component of which is genital engorgement and increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity and a subjective excitement response. Orgasm is the release of sexual tension that has culminated during arousal. Hence, Female Sexual Disorder (FSD) occurs when a woman has an absent, inadequate or unsatisfactory response in any one or more of these phases, usually desire, arousal or orgasm.
The American Psychiatric Association classifies female sexual dysfunction (FSD) into four classes: FSAD, hypoactive sexual desire disorder (HSDD), female orgasmic disorder (FOD), and sexual pain disorders (e.g. dyspareunia and vaginismus) [see the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)]. DSM-IV defines the four classes as follows:
HSDD—Persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulties. The judgement of deficiency or absence is made by the clinician, taking into account factors that affect functioning, such as age and the context of the person's life.
FSAD—Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement
FOD—Persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase. Women exhibit wide variability in the type or intensity of stimulation that triggers orgasm. The diagnosis of FOD should be based on the clinician's judgement that the woman's orgasmic capacity is less than would be reasonable for her age, sexual experience, and the adequacy of the sexual stimulation she receives.
Sexual Pain Disorders such as Dyspareunia and Vaginismus. Dyspareunia is the recurrent or persistent genital pain associated with sexual intercourse. Vaginismus is the recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with sexual intercourse.
The American Foundation for Urologic Disease has also developed definitions using the same four classes (see The Journal of Urology, 2000, Vol 163, page 888-893). The definitions are very similar to those of the DSM-IV:
1) HSDD is the persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts, and/or desire for or receptivity to sexual activity, which causes personal distress.
HSDD is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes in both pre-menopausal woman (i.e. woman who are pre-menopausal and who have not have hysterectomies) as well as post menopausal women include illness, medications, fatigue, depression and/or anxiety. Factors having a potential (conscious or sub-conscious) psychological impact such as relationship difficulties or religious factors may be related to the presence of/development of HSDD in females.
The term significant HSDD means a level of HSDD which causes some degree of personal distress to the female subject. Preferably significant HSDD means a level of HSDD which causes some degree of distress and is measurable, for example, through evaluation by a clinician using a semi-structured questionnaire.
2) FSAD is the persistent or recurrent inability to attain or maintain sufficient sexual excitement, causing personal distress, which may be expressed as a lack of subjective excitement, or genital (lubrication/swelling) or other somatic responses.
FSAD is a highly prevalent sexual disorder affecting pre-, peri-, and post menopausal women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and UG disorders. FSAD is characterized by inadequate genital response to sexual stimulation. The genitalia do not undergo the engorgement that characterizes normal sexual arousal. The vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded. FSAD can be caused by reduced estrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and arteriosclerosis. Other causes result from treatment with diuretics, antihistamines, antidepressants e.g. selective serotonin reuptake inhibitors or antihypertensive agents.
3) FOD is the persistent or recurrent difficulty, delay in or absence of attaining orgasm following sufficient sexual stimulation and arousal, which causes personal distress.
4) Sexual pain disorders: Dyspareunia is the recurrent or persistent genital pain associated with sexual intercourse. Vaginismus is the recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal penetration, which causes personal distress. Dyspareunia and vaginismus are characterised by pain resulting from penetration and sexual activity and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
The etiology of sexual dysfunction, in both men and women, may include vascular/endothelial disease such as hypertension, neurological disorders, and hormonal disorders, such as decreased levels of estrogen and/or testosterone. Sexual dysfunction in both men and women can also be caused, or exacerbated, by medication such as antidepressants, antihypertensive and many other classes of commonly used medication. Given the extensive use of these medication by all ages and both sexes it is especially important to develop means of treating medication induced sexual dysfunction.
Clearly FSD especially, is a complex disorder with more active clinical issues than the corresponding male disorder, penile erectile dysfunction (MED). Hence it is not surprising that to date there has been little success in treating FSD, and use of treatments that are successful in treating MED, such as sildenafil, have shown only limited success in ameliorating FSD. It may be that a different spectrum of activities, mechanisms, dosing regimens and duration of action of agents is needed when devising treatments for women, relative to approaches taken with men. But treatments for sexual dysfunction of all types in both men and women, with the partial exception of MED, is inadequate and thus there is a great clinical need for such treatments.